Objective To investigate the effect of ox-HDL on EPCs and underlying mechanisms.Methods Cultured human EPCs were challenged with different concentrations of ox-HDL with anti-CD36 neutralizing antibody or CD36 shRNA.Apoptosis, migration, angiogenesis in vitro and in vivo, intracellular ROS levels, and cholesterol efflux were assayed.Expressions of CD36, MAPKs and NF-κB were measured by real-time PCR, Western blot, and EMSA.Secretion of TSP-1 and VEGF in hypoxic environment was detected by ELISA.Furthermore, such inhibitory effects of ox-HDL were confirmed in hind limb ischemia models with laser doppler scanning, angiography, immunofluorescence examination and functional scoring.Results oxHDL was shown to increase apoptosis and intracellular ROS levels, but reduce migration, angiogenesis and cholesterol efflux of EPCs in a dose dependent manner.p38 MAPK and NF-κB were activated after ox-HDL stimulation, which also upregulated TSP-1 expression without affecting VEGF in hypoxic environment.All effects exerted by ox-HDL could be significantly attenuated by pretreatment with anti-CD36 neutralizing antibody or shRNA-mediated CD36 knockdown.Data of in vivo experiments and the inversely correlation of ox-HDL and circulating EPC numbers among CAD patients also supported it.Conclusion These findings suggested ox-HDL would impair EPCs function by activating CD36-p38 MAPK-NF-κB pathway and then abnormally increasing oxidative stress and TSP-1 secretion, which was in accord with the inverse relationship between ox-HDL and circulating EPCs and might be one of potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.